The present invention relates to adhesives suitable for use as bioadhesives and which comprise both adhesive polymer and plasticiser.
Various applications for bioadhesives exist, including medical tape and transdermal patches, for example. Methods of manufacture of these products are well advanced, but the nature of the adhesive remains a problem.
If the adhesive on medical tape is too strong, then removal can be painful, and will also serve to exfoliate the skin, which can cause irritation and may even lead to sensitisation to any drugs that the patient might be taking.
If the bioadhesive is too weak, then the patch or tape will tend to come away from the skin before it should. This has led to bioadhesives being developed which have merely been adapted so as not to be too strong to be painful, and not so weak as to be relatively useless.
More recently, it has been established that strong adhesives can be tempered with plasticisers. These generally take the form of oil substances introduced into the adhesive polymer. The effect of the introduction of such oily substances is to soften the physical structure of the adhesive whilst, at the same time, acting at the interface between the adhesive and the skin, thereby helping to somewhat weaken the adhesive, and to prevent exfoliation. Such a beneficial type of adhesive was first noted in certain types of electrical insulating tape.
The problem with such softened, or plasticised, adhesives is that, once they are weak enough to be medically acceptable, their cohesive strength is poor. Thus, such adhesives, when used in transdermal patches or surgical tape, for example, have insufficient integrity, and tend to tear, leaving bits of adhesive behind on the skin.
EP-A-450986 discloses an acrylic adhesive plasticised with isopropyl myristate (IPM) and which also contains nitroglycerine, which can further serve as a plasticiser. In order to improve cohesion of this adhesive, cross-linking was effected with aerosil silica. The problem with such cross-linking is the technical difficulty involved in sufficiently finely dividing the aerosil silica and incorporating it uniformly throughout the adhesive. Such cross-linking would not be generally practical.
U.S. Pat. No. 5,298,258 more generally seeks to solve the problems noted above, and discloses acrylic adhesives containing substantial amounts of plasticisers. Various methods for cross-linking the adhesive are mentioned, including irradiation and exposure to UV, but chemical cross-linking with a metal alcoholate, metal chelate or trifunctional isocyanate is preferred. The cross-linking of such an adhesive requires the presence of active hydrogen, generally in the form of a carboxyl or hydroxyl group, typically provided by a co-monomer having the required functionality.
The problem with such a system is with regard to the nature of the cross-linking, where there is necessarily involved an active chemical reagent, either on the adhesive (carboxyl groups, for example) or in the cross-linker (such as aluminium in aluminium alcoholate). Many drugs can react or interact with such groups, which can lead to problems, such as breakdown of the drug, or simple blocking of the cross-linking. For example, where a drug is weakly basic, then this can interact with the carboxyl groups present on the adhesive, thereby competing with the cross-linker.
WO 99/02141 discloses block copolymers wherein the soft segments are cross-linked, these copolymers being suitable for use as drug-retaining bioadhesives in transdermal patches. These adhesives suffer a loss of cohesion, however, when a plasticiser is incorporated.
It has now, surprisingly, been found that it is possible to provide a satisfactory medical adhesive with good cohesion and adhesion properties and low irritation which comprises an adhesive polymer and a plasticiser, wherein the polymer is cross-linked by a polyamine reacting with ketone groups present in the adhesive. Such adhesives are also useful in other non-medical applications where it is desired to apply an area of material, such as a patch or tape, for what may be only a limited period of time.
Thus, in a first aspect, the present invention provides an adhesive material suitable for use as a bioadhesive and comprising an adhesive polymer and a plasticiser therefor, wherein the adhesive is cross-linked, characterised in that the adhesive comprises ketone groups cross-linked by a polyamine cross-linking agent.
For the avoidance of doubt, the present invention encompasses novel adhesive materials, as disclosed herein, wherein the polymer and/or copolymer constituents thereof are cross-linked, wherein at least a portion of the cross links comprise a moiety
 greater than Cxe2x95x90Nxe2x80x94(X)xe2x80x94Nxe2x95x90C less than 
in which the carbon atoms are each a part of the respective polymer and/or copolymer constituents and each X is the same or different, preferably the same, and is directly equivalent to any group that would serve to carry the necessary amine groups of a polyamine cross-linking agent of the present invention.
Accordingly, it will be appreciated that X need not necessarily exist, in the instance of hydrazine, for example. It will also be appreciated that more than two suitable amine groups may be attached to X, although X may often be of the form X1xe2x80x94N less than , or of the form X2(NAxe2x80x94)2, wherein X1 and X2 represent the kernel of X, and the groups xe2x80x94N less than  and NA represent the links with xe2x80x94Nxe2x95x90C less than  groups, with each A representing a hydrogen or a direct bond with X2.
Bioadhesive materials of the present invention have been found to possess good water vapour permeabilities, which allows the skin to breathe when the tape or patch is in place. In addition, the lack of any necessary reactive groups is useful for drug stability, and also in providing certain sorts of patch that could not previously be made, as the bioadhesives of the invention are generally susceptible to very little interaction with other materials.
It will be appreciated that the adhesive polymers of the present invention are not restricted to the nature of the application, and that any reference to a specific embodiment, such as tape, or a patch, should be construed as incorporating reference to any other possible embodiment incorporating an adhesive of the invention, mutatis mutandis, where appropriate.
The nature of the adhesive polymer is not critical to the present invention. Indeed, the term xe2x80x9cpolymerxe2x80x9d is used generically herein to relate to polymers, copolymers and mixtures thereof.
In general, it is preferred that the polymer should be a synthetic polymer, in order to be able to provide adequate quality control and predictability of results. It is also advantageous to use synthetic polymers, as they can be controlled to contain desired side-groups, as necessary. In the present invention, the adhesive polymer, or a substantial component thereof, has at least one ketone group which is able to react with a polyamine.
Ketone groups are capable of tautomerisation, where there is an equilibrium between the ketone and the corresponding enol compound. This equilibrium is generally in favour of the ketone. In the present invention, it is strongly preferred that the ketone-containing polymer should have at least one ketone group with little or substantially no tendency to enolisation. Hence, it is preferred that the ketone group should not be part of a larger functionality, and it is particularly the case that the ketone group should not be part of a carboxyl group or any derivative thereof, such as an esteric linkage or amide group, although it may be linked to or adjacent such a group. It is also strongly preferred that the ketone group should not be part of an aldehyde group.
It appears that, in the present invention, the cross-linking reaction takes place between the keto form of the carbonyl group and the amine group of the cross-linking agent. It has been found that, if the ketone group is not stable in the keto form, then it reacts only poorly, if at all, with the cross-linking agent. Preferred compounds are those in which the keto form is at least 100 fold more stable than the enol form, preferably more stable by a factor of 104, most preferably more stable by a factor of 106 or greater. Preferably the equilibrium constant K (enol/keto), when measured in water, is less than 10xe2x88x922, more preferably less than 10xe2x88x924, and most preferably less than 10xe2x88x926, or even smaller. In this way, the equilibrium is strongly biased in favour of the keto form. Other factors aside, the more strongly biased the equilibrium toward the ketone group, the better.
Given the preference for the ketone group to not readily be able to form an enol group, then it will be appreciated that functionalities in the proximity of the reactive ketone group are preferred which do not encourage the keto group to enolise. In fact, such functionalities are preferred where stabilisation of the keto group is encouraged.
Block copolymers are useful in the present invention. Suitable block copolymers consist of a mixture of xe2x80x98hardxe2x80x99 (A) and xe2x80x98softxe2x80x99 (B) segments, which may be combined in an A-B-A or (A-B)n type structure (c.f. Block Copolymers: Overview and Critical Survey, Noshay and McGrath, 1977). Association of the hard segments is thought to provide a degree of physical cross-linking, which improves the cohesive properties of the adhesive. Acrylic block copolymers, comprising soft and hard segments, having a degree of chemical cross-linking between the soft segments, are preferred.
More specifically, the term xe2x80x98block copolymerxe2x80x99, as used herein, refers to a macromolecule comprised of two, or more, chemically dissimilar polymer structures, terminally connected (Noshay and McGrath, supra). These dissimilar polymer structures, sections or segments, represent the xe2x80x98blocksxe2x80x99 of the block copolymer, the A and B segments comprising the chemically distinct polymer segments of the block copolymer. In the present invention, the A-B-A structure is preferred.
In general, it is preferred that the adhesive possesses a minimum number of functionalities having active hydrogen, in order to avoid undesirable reactions/interactions, such as with any drug that it is desired to incorporate into the bioadhesive material. It will be appreciated that this is only a preferred restriction, and that any adhesive may be tailored by one skilled in the art to suit individual requirements. For example, it may be desirable to incorporate certain active groups into the adhesive in order to encourage uptake of a given compound, such as a drug. It is also the case that, where the adhesive is not intended for medical use, restrictions on any medically undesirable function are not so severe. Where the adhesive is used as an adhesive in its own right, without carrying a drug, such as in medical or surgical tape, then it is also less of a requirement to limit active functionalities, although limiting such functionalities generally helps to reduce irritation and, so, is preferred.
Limiting active functionalities, especially those with active hydrogen, is generally preferred, in order to permit wide use of any given formulation of adhesive without having to take into account how it is likely to interact, chemically, with its environment. However, as stated above, an adhesive required for any individual purpose may be tailored as seen fit by one skilled in the art. Thus, a generally chemically inert adhesive is preferred, in the absence of requirements to the contrary.
It will be appreciated that the term xe2x80x98drugxe2x80x99, as used herein, refers to any substance or compound suitable for administration via the adhesive of the invention, typically a transdermal patch. A substance having drug retention properties is taken herein as being a substance capable of absorbing or adsorbing a drug. In the instance where the substance is loaded with drug for dispensing via a transdermal patch, then it will be appreciated that such absorbance and/or adsorbance should be at least partially reversible.
Adhesives of the present invention are particularly of use in medical and veterinary applications, although the latter may tend to suffer from the disadvantage of the animal endeavouring to remove the dressing or tape. Tapes employing the adhesives of the invention exhibit good adhesion and cohesion, and release freely from the subject without painful exfoliation. It will be appreciated that, while tapes will not necessarily carry drugs, it may be beneficial for a tape to carry such agents as antimicrobial agents.
Preferred adhesives of the invention are those which, in tests, can be applied to newspaper and readily removed therefrom without tearing the paper. Particularly preferred are those adhesives which can be removed from, and reapplied to, newspaper repeatedly, without losing adhesion or damaging the paper. Tapes having such properties are particularly useful, and are preferred embodiments of the present invention.
Suitable examples of drug-impermeable backings which may be used for transdermal patches include films or sheets of polyolefins, polyesters, polyurethanes, polyvinyl alcohols, polyvinyl chlorides, polyvinylidene chloride, polyamides, ethylene-vinyl acetate copolymer (EVA), ethylene-ethylacrylate copolymer (EEA), vinyl acetate-vinyl chloride copolymer, cellulose acetate, ethyl cellulose, metal vapour deposited films or sheets thereof, rubber sheets or films, expanded synthetic resin sheets or films, non-woven fabrics, fabrics, knitted fabrics, paper and foils. Other backings will be readily apparent to those skilled in the art.
Breathability is important, and it is generally preferred that, while the backing material is strong, it should also be able to allow the passage of water vapour, at least in medical applications. In the case of transdermal patches, water vapour permeability can be tempered by the requirement for drug-impermeability.
Adhesives of the present invention are also particularly useful in the construction of patches for transdermal delivery of drugs. It will be readily apparent to those skilled in the art which adhesives will be suitable for this purpose, and examples are given below. A highly preferred type of adhesive corresponds to those disclosed in WO 99/02141 (supra), incorporated herein in its entirety. Where the adhesive does not already possess a suitable ketone group, this can readily be provided by the incorporation of a suitable monomer when preparing the polymer. The adhesives of WO 99/02141 already possess good cohesion and adhesion, but addition of plasticiser compromises cohesion. Cross-linking in accordance with the present invention enables the use of these adhesives, retaining their superior drug retention properties and allowing control of the level of adhesion, while allowing painless and irritation-free removal of the patch.
Other applications of the adhesives of the present invention include adhesive tapes for temporarily securing the tape or another object to a delicate surface. Adhesion is good, yet removal of the tape may be readily performed without damaging the delicate surface. The adhesive may also be used for jotter-type applications, for example, where a suitable writing surface, such as paper or plastic, can be temporarily fixed to any surface. Using the adhesives of the present invention means that the user does not have to be concerned where the jotter note is stuck, as removal is easy without damage to any conventional surface.
Many adhesives are known, and it will be apparent to those skilled in the art which adhesives will be useful in the present invention. In general, those based on acrylates and methacrylates are preferred and alkyl acrylates and alkyl methacrylates provide properties of tack and adhesion. Suitable alkyl acrylates and alkyl methacrylates include n-butyl acrylate, n-butyl methacrylate, hexyl acrylate, 2-ethylbutyl acrylate, isooctyl acrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate and tridecyl methacrylate, although other suitable acrylates and methacrylates will be readily apparent to those skilled in the art. Acrylate block copolymers are suitably used in the present invention, and it is preferred that the acrylic block copolymer comprises at least 50% by weight of alkyl acrylate or alkyl methacrylate (co) polymer.
Particularly where the adhesive is for use in a transdermal patch, it is often preferred that a polar monomer is copolymerised with an alkyl acrylate or alkyl methacrylate, in order to enhance the solubility of certain drugs. Suitable such polar monomers include hydroxyethyl acrylate, hydroxypropyl acrylate, vinyl pyrrolidone, acrylamide, dimethylacrylamide, acrylonitrile, diacetone acrylamide and vinyl acetate.
Diacetone acrylamide, or a combination of diacetone acrylamide and vinyl acetate, is useful in the present invention. The diacetone acrylamide component enables more advantageous drug loading capabilities than vinyl acetate, but vinyl acetate enhances the rate of polymerisation, which is of commercial importance. In such a case, where two polar monomers are used in an adhesive, it will be appreciated that the levels of each monomer may be manipulated in such a way as to provide optimum drug retention and delivery.
Where used, it is preferred that diacetone acrylamide, or other polar monomer, such as hydroxyethyl methacrylate or vinyl acetate, be present in no more than 50% w/w of the monomeric mix, as this can lead to reduced adhesion, for example. However, where adhesion is not important, good levels of drug loading may be obtained with an excess of polar monomer.
In general, it is preferred to provide the adhesive in the form of a copolymer. In the preferred block copolymers, it is preferred that at least the soft segment should be a copolymer. This not only has the advantage of giving a greater variety of polymers from which to select, but is also useful in providing the necessary ketone groups. Suitable monomers (comonomers) will be readily apparent to those skilled in the art and, essentially, are only otherwise limited to compounds which are copolymerisable in the system of choice and which provide the necessary ketone group.
Examples of suitable ketone-providing monomers include aliphatic, olefinically unsaturated keto, preferably monoketo, compounds such as vinyl esters of allyl esters of aliphatic monobasic or dibasic acids containing a keto group and having a suitable number of carbon atoms, such as three to eight. Suitable such acids include pyruvic acid, acetoacetic acid and levulinic acid, a suitable ester of such being the vinyl alcohol ester. For example, one suitable compound, pyruvic acid vinyl alcohol ester, has the formula H2Cxe2x95x90CHxe2x80x94Oxe2x80x94COxe2x80x94COxe2x80x94CH3.
Other suitable compounds include aliphatic amides substituted at the nitrogen by a vinyl or allyl group and other suitable monomers are the olefinically unsaturated ketones, such as vinylmethyl ketone and vinylethyl ketone. However, the currently preferred monomer is diacetone acrylamide, which is readily commercially available and which has the structure CH2xe2x95x90CHxe2x80x94CONHxe2x80x94C(CH3)2xe2x80x94CH2xe2x80x94COCH3. A particularly preferred embodiment of the adhesive of the present invention uses a combination of butyl acrylate, 2-ethylhexyl acrylate and diacetone acrylamide, preferably in a ratio of about 4:4:3, either as the adhesive, or as the soft segment of the block copolymer, although other suitable preparations will be apparent to those skilled in the art. In general, unless otherwise specified, ratios and percentages, as given herein, are by weight.
The present invention is not limited to specific plasticisers. The only requirement for the plasticisers is that it be appropriate to the adhesive. For example, using the preferred adhesive noted above, naturally occurring castor oil has been found not to be appropriate, for example, as it leaks out of the adhesive, thereby preventing adhesion. However, appropriate plasticisers are readily established by those skilled in the art. In particular, a simple mixture of a plasticiser with the adhesive should provide a bioadhesive material, or material suitable for use as a bioadhesive (which expressions are used interchangeably herein), which does not separate, and which is adhesive, within the broad general ranges that have generally been noted. Too little plasticiser will generally result in an adhesive material which is too strong and insufficiently soft, while too much plasticiser will generally lead to disruption of the adhesive and permit insufficient adhesive quality.
In general, the plasticiser may be used in an amount generally between about 20 and 200% of the adhesive, more specifically between about 40% and 160%, preferably between about 60 and 120%, with about 100% generally providing good results. It will be appreciated, however, that different plasticisers will have different optima for different adhesives.
Plasticisers are generally liquids having high boiling points, and suitable examples include glycols, such as ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, polyethylene glycol and polypropylene glycol; fats and oils such as olive oil, castor oil, squalene and lanolin; organic solvents such as dimethyl decyl sulphoxide, methyl octyl sulphoxide, dimethyl sulphoxide, dimethylformamide, dimethylacetamide, dimethyllaurylamide, dodecyl pyrrolidone and isosorbitol; liquid surfactants; specific plasticisers such as diisopropyl adipate, phthalates and diethyl sebacate; hydrocarbons such as liquid paraffin; ethoxylated stearyl alcohol, glycerol esters, isopropyl myristate, isotridecyl myristate, ethyl laureate, N-methylpyrrolidone, ethyl oleate, oleic acid, isopropyl adipate, isopropyl palmitate, octyl palmitate and 1,3-butanediol. Of the above, phthalates, isopropyl myristate, isotridecyl myristate and octyl palmitate are currently preferred. These substances can be used either alone or as a mixture or mixtures thereof.
Polyamines for use in the present invention should have two or more free amine groups to react with the ketone moiety of the adhesive. In the simplest embodiment, hydrazine, or hydrazine hydrate, may be used as the polyamine. However, we have established that it is highly preferable that the reactive amine should be bound directly to another nitrogen, or to another group providing the same or generally equivalent electronegativity as another nitrogen. Thus, dihydrazine compounds and linked amine compounds are particularly preferred. Examples of the latter include dialkyl triamines, especially diethylene triamine, but other suitable triamine and polyamine compounds will be readily apparent to those skilled in the art.
Dihydrazine compounds are especially preferably dihydrazides of polybasic organic acids, especially dicarboxylic acids. Examples of aromatic dicarboxylic acids include phthalic acid, isophthalic acid and terephthalic acid, although others will be readily apparent to those skilled in the art. Particularly preferred dihydrazides are those of aliphatic saturated dicarboxylic acids, especially those having 2-10 carbon atoms, and dihydrazides of oxalic acid and sebacic acids are suitable examples, while the dihydrazide of adipic acid is currently preferred (also known as adipic acid diamine and adipohydrazide). It will be apparent that polyhydrazides may also be employed.
We prefer that the polyamines be used in an amount generally between about 0.05% and 2% of the adhesive, more specifically between about 0.3% and 1%, although individual polyamines will have different optima for different adhesives. In addition, it will be appreciated that the quantity of the polyamine that is required may vary depending upon the amount of plasticiser that is used. We prefer that the amount of crosslinker that is added results in gelation of the adhesive, and is such that the adhesive cannot be subsequently dissolved by a solvent after crosslinking.
Polymers suitable for use as the hard portion of the block copolymer possess glass transition temperatures above room temperature. Suitable monomers for use in forming the hard segment polymer include styrene, xcex1-methylstyrene, methyl methacrylate and vinyl pyrrolidone, although other suitable monomers will be readily apparent to those skilled in the art. Polystyrene and polymethyl methacrylate have been found to be suitable for the present invention.
It is preferred that the hard portion of the block copolymer forms from 3-30% w/w of the total block copolymer, particularly preferably from 5-15% w/w.
Particularly suitable block copolymers have soft portions which have been at least partially chemically cross-linked prior to cross-linking with polyamine. Such initial cross-linking may be effected by any suitable cross-linking agent. It is particularly preferable that the cross-linking agent be in the form of a monomer suitable for incorporation into the soft segment during polymerisation. Preferably the cross-linking agent has two, or more, radically polymerisable groups, such as a vinyl group, per molecule of the monomer, at least one tending to remain unchanged during the initial polymerisation, thereby to permit cross-linking of the resulting block copolymer.
Suitable initial cross-linking agents for use in the present invention include divinylbenzene, methylene bis-acrylamide, ethylene glycol di(meth)acrylate, ethylene glycol tetra(meth)acrylate, propylene glycol di(meth)acrylate, butylene glycol di(meth)acrylate, or trimethylolpropane tri(meth)acrylate, although other suitable cross-linking agents will be readily apparent to those skilled in the art. A preferred initial cross-linking agent is tetraethylene glycol dimethacrylate. It is preferred that the initial cross-linking agent comprises about 0.01-0.6% by weight of the block copolymer, with 0.1-0.4% by weight being particularly preferred.
Methods for the production of block copolymers from their monomeric constituents are well known. Block copolymer portions may be produced by any suitable method, such as step growth, anionic, cationic and free radical methods (Block Copolymers, supra). Free radical methods are generally preferred over other methods, such as anionic polymerisation, as the solvent and the monomer do not have to be purified.
Suitable initiators for polymerisation include polymeric peroxides with more than one peroxide moiety per molecule. One suitable initiator has been found to be xe2x80x98Perhexa MCxe2x80x99 (1,1xe2x80x2-di-tertbutyl-peroxy-2-methyl cyclohexane, Nihon Yusi C.C.). This compound contains two tertiary butyl peroxy groups which allow stepwise polymerisation of the hard and soft segments of the block copolymer. The initiator CH-50-AL (Peroxid-Chemie GmbH) has also been found to be suitable in the manufacture of compounds of the present invention. Choice of reaction conditions is well within the skill of one in the art, once a suitable initiator has been chosen.
The initiator is preferably used in an amount of 0.005-0.1% by weight of the block copolymer, with 0.01-0.05% by weight being particularly preferred, although it will be appreciated that the amount chosen is, again, well within the skill of one in the art. In particular, it is preferred that the amount should not be so much as to cause instant gelling of the mix, nor so low as to slow down polymerisation and to leave excess residual monomers. A preferred level of residual monomers is below 2000 ppm. It will also be appreciated that the amount of initiator will vary substantially, depending on such considerations as the initiator itself and the nature of the monomers.
It will be appreciated that there is no particular restriction on further substances being used in association with the adhesive of the invention. For example, suitable agents may be used to inhibit crystallisation of drug in the adhesive, where the adhesive is to be used in a patch, for instance. Many agents will be apparent to those skilled in the art, and polyethylene glycol is generally particularly effective. However, in general, it has been found that compounds to be delivered from patches of the invention are generally less likely to crystallise than they are in prior art systems.
Where the bioadhesive material of the present invention is to be used in association with a patch in order to hold a drug, then suitable drugs are biologically active compounds or mixtures of compounds that have therapeutic, prophylactic or other beneficial pharmacological or physiological effects.
Examples of drugs that may be used in combination with the bioadhesive material of the present invention include anti-arrhythmic drugs, anticoagulants, antidiabetics, antiepileptics, antifungals, antigout, antimalarials, antimuscarinic agents, antineoplasic agents, antiprotozoal agents, thyroid and antithyroid agents, anxiolytic sedatives and neuroleptics, beta blocking agents, drugs affecting bone metabolism, cardiac inotropic agents, chelating agents, antidotes and antagonists, corticosteroids, cough suppressants, expectorants and mucolytics, dermatological agents, diuretics, gastro-intestinal agents, general and local anaesthetics, histamine H1 and H2 receptor antagonists, nitrates, vitamins, opioid analgesics, parasympathomimetics, anti-asthma agents, muscle relaxants, stimulants and anorectics, sympathomimetics, thyroid agents, xanthines, lipid regulating agents, antiinflamatory drugs, analgesics, antiarthritic drugs, antispasmodics, antidepressants, antipsychotic drugs, tranquillisers, narcotic antagonists, antiparkinsonism agents, cholinergic agonists, anticancer drugs, immunosupressive agents, antiviral agents, antibiotic agents, appetite suppressants, antiemetics, anticholinergics, antihistamines, antimigraine agents, coronary, cerebral or peripheral vasodilators, hormonal agents, contraceptive agents, antithrombotic agents, diuretics, antihypertensive agents and cardiovascular drugs. Other drugs will be readily apparent to those skilled in the art.
Examples of specific drugs include steroids such as oestradiol, progesterone, norgestrel, levonorgestrel, norethisterone, modroxyprogestrone acetate, testosterone and their esters; nitro-compounds such as nitroglycerine and isosorbide nitrates; vitamins D2 and D3, nicotine, chlorpheniramine, terfenadine, triprobidine, hydrocortisone, oxicam derivatives such as piroxicam, ketoprofen, mucopolysaccharides such as thiomucase, buprenorphine, fentanyl, naloxone, codeine, dihydroergotamine, pizotiline, salbutamol, terbutaline, prostaglandins such as misoprostol and enprostil, omeprazole, imipramine, benzamides such as growth releasing factor and somatostatin, clonidine, dihydropyridines such as nifedipine, verapamil, ephidrine, pindolol, metoprolol, spironolactone, nicardipine hydrochloride, calcitriol, thiazides such as hydrochlorothiazide, flunarizine, sydononimides such as molsidomine, sulphated polysaccharides such as heparin fractions, as well as pharmaceutically acceptable equivalents thereof and pharmaceutically acceptable esters and the salts of such compounds with pharmaceutically acceptable acids and bases as appropriate. It will be appreciated that, while various drugs have been exemplified above, some drugs are more suitable for use in transdermal delivery systems than others. While a transdermal delivery system may deliver a quantity of a drug, this quantity may not be the optimum therapeutic dose. Essentially, any drug that can be delivered by a patch and which does not substantially crystallise at levels too low to be useful is envisaged as being useful in patches of the present invention.
It will be appreciated that, while various drugs have been exemplified above, some drugs are more suitable for use in transdermal delivery systems than others. While a transdermal delivery system may deliver a quantity of a drug, this quantity may not be the optimum therapeutic dose.
In general, the adhesive polymer may be prepared in any suitable manner as known in the art. This will generally comprise the adhesive being prepared in a solvent and, prior to removal of the solvent, it is preferable to involve, as a final step, the polyamine. This is mixed with the prepared adhesive solution and then applied to the tape or patch, or any other suitable application requiring such an adhesive material. A further advantage of the present invention is that the cross-linking time is generally substantially reduced, so that manufacture is easier. The solvent can be removed as known in the art.
The preferred adhesive strength of the bioadhesive material is such that, when applied to a tape or patch, the tape or patch can be applied to the skin and then removed without removing the stratum corneum layer of the skin surface. In particular, an adhesive strength of about 30 g/inch (xcx9c1.2 g/mm) to about 300 g/inch (xcx9c12 g/mm), more preferably about 40 g/inch (xcx9c1.6 g/mm) to about 200 g/inch (xcx9c8 g/mm), is preferred for the bioadhesive, although the skilled person will recognise appropriate strengths. Materials with adhesive strength greater than about 300 g/inch (xcx9c8 g/mm) are likely to cause skin irritation when the tape is removed, as the outer skin layer is concomitantly removed.
It will be appreciated that the present invention further provides a process for the manufacture of adhesive materials as described herein, comprising preparing an adhesive material comprising substantially non-enolisable ketone groups, blending said material with a suitable plasticiser therefor and, at the same time, or thereafter, further blending therewith a polyamine cross-linking agent and allowing the mixture to complete the cross-linking reaction. The adhesive material will normally be prepared in solution, prior to the addition of plasticiser and polyamine. Cross-linking will normally be done under conditions of heat.
The present invention will now be illustrated further with reference to the following, non-binding Examples and Comparative Examples.